Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway

Accounts of Chemical Research
Hao Lu, Peter J Tonge

Abstract

The modern age of drug discovery, which had been slowly gathering momentum during the early part of the twentieth century, exploded into life in the 1940s with the isolation of penicillin and streptomycin. The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated. However this initial optimism was misplaced, and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health. Drug resistance arises through the unrelenting pressure of natural selection, and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms. In this Account, we summarize current progress in developing inhibitors of FabI, the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II), a validated but currently underexploited target for drug discovery. The FabI inhibitors have been divided into two groups, based on whether they form a covalent adduct with the NAD (+) cofactor. Inhibitors that form a covalent adduct include the d...Continue Reading

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